Combination treatment for acute myocardial infarction

ABSTRACT

A combination therapy for the treatment of acute myocardial infarction comprises administering a combination of a thrombolytic agent and levosimendan or a pharmaceutically acceptable salt thereof to a patient. The combination synergistically reduces mortality of patients with acute myocardial infarction.

TECHNICAL FIELD

The present invention relates to a method for treating myocardialinfarction, by administering a synergistic combination of a thrombolyticagent and levosimendan or a pharmaceutically acceptable salt thereof toa patient in need of such treatment. The invention also relates to amedical product comprising a thrombolytic agent and levosimendan or apharmaceutically acceptable salt thereof as a combined preparation.

BACKGROUND OF THE INVENTION

Myocardial infarction is an important complication of coronary arterydisease and usually results from a critical reduction in coronary bloodflow secondary to coronary thrombosis. Intravenous thrombolytic agenttherapy has been widely used to restore flow to the occluded coronaryartery. A thrombolytic agent is a medicament capable of lysing thefibrin-platelet thrombus, and thereby permitting blood to again flowthrough the affected blood vessel. Such agents include streptokinase,urokinase, prourokinase, reteplase, alteplase and tissue-typeplasminogen activator (t-PA). The mortality of patients with acutemyocardial infarction even if treated with thrombolytic agents remainshigh.

Levosimendan, which is the (−)-enantiomer of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,and the method for its preparation is described in EP 565546 B1.Levosimendan is potent in the treatment of heart failure and hassignificant calcium dependent binding to troponin. Levosimendan isrepresented by the formula:

The hemodynamic effects of levosimendan in man are described inSundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066 and inLilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl. 1), S63-S69,1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosingis described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol.,26(Suppl. 1), S57-S62, 1995. The use of levosimendan in the treatment ofmyocardial ischemia is described in WO 93/21921. The use of levosimendanin the treatment of pulmonary hypertension is described in WO 99/66912.The use of levosimendan in the treatment or prevention of coronary graftvasospasm in described in WO 01/00211. Levosimendan solutions suitablefor intravenous use have been described in WO 01/19334. Clinical studieshave confirmed the beneficial effects of levosimendan in congestiveheart failure patients.

SUMMARY OF THE INVENTION

It has now been found that administration of a thrombolytic agenttogether with levosimendan has a beneficial synergistic effect on themortality of patients treated for myocardial infarction. Therefore, thecombination is particularly useful for the treatment of acute myocardialinfarction.

Thus, in one aspect the present invention provides a method for thetreatment of acute myocardial infarction, which comprises thesimultaneous, separate or sequential administration of an effectiveamount of a thrombolytic agent and levosimendan or a pharmaceuticallyacceptable salt thereof to a patient in need thereof.

In another aspect the present invention provides a method for thetreatment of acute myocardial infarction, said method comprisingadministering to a patient in need thereof a thrombolytic agent incombination with levosimendan or a pharmaceutically acceptable saltthereof.

In another aspect the present invention provides a method for reducingmortality of patients with acute myocardial infarction, which comprisesthe simultaneous, separate or sequential administration of an effectiveamount of a thrombolytic agent and levosimendan or a pharmaceuticallyacceptable salt thereof to a patient in need thereof.

In another aspect the invention provides a method for reducing mortalityof patients with acute myocardial infarction, which comprisesadministering to a patient in need thereof a thrombolytic agent incombination with levosimendan or a pharmaceutically acceptable saltthereof.

In another aspect the invention provides a medical product comprising,separately or together, as active ingredients a thrombolytic agent andlevosimendan or a pharmaceutically acceptable salt thereof as a combinedpreparation.

In another aspect invention provides a pharmaceutical compositioncomprising as active ingredients a thrombolytic agent and levosimendanor a pharmaceutically acceptable salt thereof.

In another aspect the invention provides the use of a thrombolytic agentand levosimendan or a pharmaceutically acceptable salt thereof as activeingredients in the manufacture of a combined preparation forsimultaneous, separate or sequential administration.

In still another aspect the invention provides use of a thrombolyticagent and levosimendan or a pharmaceutically acceptable salt thereof asactive ingredients in the manufacture of a medicament for reducingmortality of patients with myocardial infarction.

DETAILED DESCRIPTION OF THE INVENTION

The method of the invention relates to a combination therapy for moreeffective treatment of acute myocardial infarction. The present methodprovides a treatment, which improves the overall clinical outcome ofpatients treated with a thrombolytic agent by administering levosimendanin combination with a thrombolytic agent. In particular, the combinationtreatment of the invention is able to synergistically reduce mortalityof acute myocardial infarction patients.

The terms “treatment” or “treating” as used herein refers to reductionin severity or frequency of symptoms and/or their underlying cause,improving the clinical outcome of a patient, prevention of theoccurrence of the symptoms and/or their underlying cause, andimprovement or remediation of damage.

The term “acute myocardial infarction” is defined as immediate or sudden(not chronic) infarction of the heart muscle, i.e. an insufficiency ofarterial blood flow as a result of occlusion of a coronary artery due toat least partial blockage of the artery by an embolus or thrombus. Asused herein, “thrombus” or “embolus” refer to a blood clot within theblood vessel. “At least partial” blockage of the artery means that theartery contains an embolus or thrombus, which reduces the crosssectional area of the artery.

The term “thrombolytic agent” is meant to refer to any agent effectivein helping to dissolving or breaking up an occluding thrombus. Athrombolytic agent may be selected from those thrombolytic agents, whichare known in the art. These include, but are not limited to,streptokinase, urokinase, prourokinase, alteplase, reteplase,anistreplase and tissue plasminogen activator (t-PA) and biologicallyactive variants thereof. A combination of two or several thrombolyticagents may be also used.

The active ingredients are preferably administered concurrently as soonas possible, preferably within six hours, after the onset of symptoms ofan acute myocardial infarction. If it is desired to avoid othermedication during the thrombolytic therapy, which may be given e.g. asan intravenous bolus or infusion, levosimendan may be administeredsequentially after the administration of the thrombolytic agent.

While it is preferred to administer levosimendan during or immediatelyafter the thrombolytic therapy, it has been found that the synergisticeffect of the combination is still obtained, if levosimendanadministration is started not later than five days, preferably not laterthan three days, more preferably not later than 48 hours, from thethrombolytic therapy or, preferably, from the onset of symptoms of anacute myocardial infarction.

If desired, levosimendan administration may also be given before thethrombolytic therapy. However, in general, thrombolytic therapy shouldbe started as soon as possible once the condition of a blocked arteryhas been diagnosed. Therefore, it is preferred that, in case ofsequential administration, the treatment method according to theinvention comprises a first step of administering an effective amount ofa thrombolytic agent and a second step of administering an effectiveamount of levosimendan, wherein the time period between the twotreatments is not more than five days, preferably not more than threedays, more preferably not more than 48 hours.

The administration routes of the active ingredients include, but are notlimited to, enteral, e.g. oral or rectal, or parenteral, e.g.intravenous, intramuscular, intraperitoneal or transdermal. In thetreatment of myocardial infarction, the active ingredients arepreferably administered parenterally, intravenous route beingparticularly preferred. Single or multiple dosages may be given.Preferably, the active agents are administered via continuous infusion.

Preferably, the method comprises administering to a patient an amount ofthe combination, which is synergistically effective in reducingmortality of patients with myocardial infarction.

Levosimendan may be administered intravenously using an infusion ratewhich is from about 0.05 to 0.4 μg/kg/min. For an intravenous bolus asuitable dose is in the range from about 5 to 30 μg/kg. In the treatmentof patients with acute myocardial infarction an intravenous bolusfollowed by continuous infusion may be needed.

Levosimedan may be administered orally to man in daily dose ranging fromabout 0.1 to 8 mg given once a day or divided into several doses a day,depending on the age, body weight and condition of the patient. Theeffective amount of levosimendan to be administered to a subject dependsupon the condition to be treated, the route of administration, age,weight and the condition of the patient.

Preferred thrombolytic agents include streptokinase, urokinase,prourokinase, alteplase, reteplase, anistreplase and tissue plasminogenactivator (t-PA) and biologically active variants thereof as well as anycombinations thereof. The thrombolytic agent may be administered usingthe conventional dosage ranges for these agents, for example a dailydosage used when the agent is administered in thrombolytic therapy as amonotherapy. The range will, of course, vary depending on thethrombolytic agent employed. Examples of normal dosage ranges are asfollows: urokinase—500,000 to 6,250,000 units/patient;streptokinase—140,000 to 2,500,000 units/patient; prourokinase—5,000 to100,000 units/patient; anistreplase—10 to 100 units/patient; t-PA—0.5 to2.0 mg/kg body weight.

Thrombolytic therapy is typically given as an intravenous bolus alone orfollowed by intravenous infusion or as an infusion alone. The infusionis normally administered over a time ranging from less than one hour toabout 12 hours, typically from about 1 to 3 hours. For example, thethrombolytic therapy may comprise administration of up to 10% of thetotal dose as bolus injection over 1 to 5 minutes and the remaining 90%then as a constant infusion during the next hour.

When the symptoms have been alleviated to the desired level, treatmentcan be stopped.

The combination may be supplemented with one or more other activeingredients, e.g. anticoagulants, or surgical methods such asangioplasty.

The active ingredients can be formulated into pharmaceutical dosageforms suitable for the treatment according to the present inventionusing the principles known in the art. They are given to a patient assuch or preferably in combination with suitable pharmaceuticalexcipients in the form of tablets, granules, capsules, suppositories,emulsions, suspensions or solutions whereby the contents of the activecompound in the formulation is from about 0.5 to 100% per weight.Choosing suitable ingredients for the composition is a routine for thoseof ordinary skill in the art. It is evident that suitable carriers,solvents, gel forming ingredients, dispersion forming ingredients,antioxidants, colours, sweeteners, wetting compounds, releasecontrolling components and other ingredients normally used in this fieldof technology may be also used.

The active ingredients may be formulated in the same pharmaceuticalformulation. Preferably, such pharmaceutical composition of thrombolyticagent and levosimendan is adapted to intravenous administration. Suchcompositions may be prepared for storage by mixing these compounds withoptional pharmaceutically acceptable carriers, excipients orstabilizers, e.g. into the form of infusion concentrates or aqueoussolutions, or powders adapted to be reconstituted with sterile water oraqueous infusion vehicles for infusion.

Alternatively, the active ingredients are formulated as separatepharmaceutical dosage forms. The combination of the two pharmaceuticaldosage forms may be packaged as a single medical product or kit for usein the method of the invention, optionally together with a packageinsert instructing to the correct use of the medical product.

Formulations suitable for intravenous administration such as injectionor infusion formulation, comprise sterile isotonic solutions of theactive ingredient and vehicle, preferably aqueous solutions. Typicallyan intravenous infusion solution of levosimendan comprises from about0.01 to 0.1 mg/ml of levosimendan. Levosimendan composition as storedbefore use is preferably an infusion concentrate product, which can bereconstituted with sterile water or aqueous infusion vehicle forinfusion. Levosimendan solutions suitable for use in the presentinvention are described e.g. in WO 01/19334.

For oral administration of levosimendan in tablet form, suitablecarriers and excipients include e.g. lactose, corn starch, magnesiumstearate, calcium phosphate and talc. For oral administration in capsuleform, useful carriers and excipients include e.g. lactose, corn starch,magnesium stearate and talc. For controlled release oral compositionsrelease controlling components can be used. Typical release controllingcomponents include hydrophilic gel forming polymers such ashydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylcelluloses, alginic acid or a mixture thereof; vegetable fats and oilsincluding vegetable solid oils such as hydrogenated soybean oil,hardened castor oil or castor seed oil (sold under trade name CutinaHR), cotton seed oil (sold under the trade names Sterotex or Lubritab)or a mixture thereof; fatty acid esters such as triglycerides ofsaturated fatty acids or their mixtures e.g. glyceryl tristearates,glyceryl tripalmitates, glyceryl trimyristates, glyceryl tribehenates(sold under the trade name Compritol) and glyceryl palmitostearic acidester.

Tablets can be prepared by mixing levosimendan with the carriers andexcipients and compressing the powdery mixture into tablets. Capsulescan be prepared by mixing levosimendan with the carriers and excipientsand placing the powdery mixture in capsules, e.g. hard gelatin capsules.Typically a tablet or a capsule comprises from about 0.1 to 8 mg, moretypically 0.2 to 5 mg, of levosimendan.

Thrombolytic agent compositions as used in clinical practice comprisesgenerally water as a carrier and pharmaceutical adjuvants known in theart, i.e. isotonizing agents; acid, base or buffer substances to adjustthe pH of the solution; and stabilizing agents for the thrombolyticagent. Said thrombolytic agent composition as stored before use ispreferably a sterile lyophilized product, which can be reconstitutedwith sterile water for injection.

The concentration of the thrombolytic agent in the composition dependson the nature of the thrombolytic agent. For example, tissue plasminogenactivator may be present in an amount from 20 mg to 100 mg per dosageform. The concentration of tissue plasminogen activator in a lyophilizedproduct is typically in the range of from 1.5 to 2% (w/w). As pHadjusting agents, phosphoric acid and optionally sodium hydroxide may beused, so that upon reconstitution with sterile water for injection, a pHof about 7.3 is reached. As stabilizing agent for the thrombolyticagent, an amino acid may be used, for example L-arginine in the case oftissue plasminogen activator. The stabilizing agent makes up the bulk ofthe lyophilized thrombolytic agent, typically from about 70% to about80% (w/w).

Examples of preferred products according to the present invention arethose wherein the thrombolytic preparation and levosimendan solution aremiscible and, when mixed, form a stable formulation for up to eighthours at room temperature. The two formulations can then be storedtogether, but in separate containers such as vials, prefilled syringesand the like, and mixed immediately before use. A preferred containercomprises the thrombolytic preparation (a) and the levosimendan solution(b) separately in a two-chamber container including means to mix bothliquids. The two-chamber container is ideally a pre-filled, two-chambersyringe with bypass or similar means (e.g. a breakable seal) allowingmixing of the two separate solutions prior to administration, and whichis further adapted for use with infusion devices.

Alternatively, the separate containers may be adapted to allowadministration of the thrombolytic preparation and the levosimendansolution sequentially, e.g. such that levosimendan solution can beadministered immediately after thrombolytic administration or e.g. afterone hour from the administration of the thrombolytic agent.

Salts of levosimendan may be prepared by known methods. Pharmaceuticallyacceptable salts are useful as active medicaments, however, preferredsalts are the salts with alkali or alkaline earth metals.

PHARMACEUTICAL EXAMPLES Example 1 Concentrate Solution for IntravenousInfusion

(a) levosimendan 2.5 mg/ml (b) Kollidon PF12 10 mg/ml (c) citric acid 2mg/ml (d) dehydrated ethanol ad 1 ml (785 mg)The concentrate solution was prepared by dissolving citric acid,Kollidon PF121 and levosimendan to dehydrated ethanol in the sterilizedpreparation vessel under stirring. The resulting bulk solution wasfiltered through a sterile filter (0.22 μm). The sterile filtered bulksolution was then aseptically filled into 8 ml and 10 ml injection vials(with 5 ml and 10 ml filling volumes) and closed with rubber closures.

The concentrate solution for intravenous infusion is diluted with anaqueous vehicle before use. Typically the concentrate solution isdiluted with aqueous isotonic vehicles, such as 5% glucose solution or0.9% NaCl solution so as to obtain an aqueous intravenous solution,wherein the amount of levosimendan is generally within the range ofabout 0.001-1.0 mg/ml, preferably about 0.01-0.1 mg/ml.

Example 2 t-PA Composition in Lyophilized State

(a) t-PA 2.0% (w/w) (b) phosphoric acid 20% (w/w) (c) L-arginine 78%(w/w)

The ingredients were mixed, lyophilized and sterilized using standardmethods. The lyophilized product comprising 20, 50 or 100 mg t-PA perdosage form (vial) is reconstituted with sterile water for injection,for example to solution having concentration of 1 mg/ml.

Example 3 Oral Levosimendan Composition

Hard gelatin capsule size 3 Levosimendan 2.0 mg Lactose 198 mg

The pharmaceutical preparation in the form of a capsule was prepared bymixing levosimendan with lactose and placing the powdery mixture in hardgelatin capsule.

Experiments

Effect of the combination on the mortality of the patients with acutemyocardial infarction

Patients who had suffered from acute myocardial infarction within fivedays received placebo or a 6-hour infusion of levosimendan using a bolusof 6, 12 or 24 μg/kg and subsequent infusion of 0.1, 0.2 or 0.4μg/kg/min. Patients were divided according to whether they had receivedthrombolytic therapy or not. The 180 day mortality was measured. Theresults are shown in Table 1. It can be seen that the combinationprovided synergistic reduction in the mortality of patients with acutemyocardial infarction. TABLE 1 The mortality of patients with acutemyocardial infarction receiving levosimendan, a thrombolytic agent or acombination thereof. Event Received thrombolytic Did not receivethrombolytic Placebo Levosimendan Placebo Levosimendan (N = 16) (N = 70)(N = 86) (N = 331) n (%) 180-day 4 (25.0%) 9 (12.8%) 28 (32.6%) 82(24.8%) mortality

1. A method for the treatment of acute myocardial infarction, whichcomprises the simultaneous, separate or sequential administration of aneffective amount of a thrombolytic agent and levosimendan or apharmaceutically acceptable salt thereof to a patient in need thereof.2. A method of reducing mortality of a patient with acute myocardialinfarction, which comprises the simultaneous, separate or sequentialadministration of an effective amount of a thrombolytic agent andlevosimendan or a pharmaceutically acceptable salt thereof to a patientin need thereof.
 3. A medical product comprising, separately ortogether, as active ingredients a thrombolytic agent and levosimendan ora pharmaceutically acceptable salt thereof as a combined preparation. 4.A pharmaceutical composition comprising as active ingredients athrombolytic agent and levosimendan or a pharmaceutically acceptablesalt thereof. 5-6. (canceled)